PROJECT SUMMARY: Fibroblast growth factors (FGFs) constitute a family of 22 proteins that regulate diverse biological processes such as growth, development, differentiation, and wound repair. FGF21 is a unique metabolic hormone as it is secreted in blood from liver in response to starvation and nutrient deprivation to stimulate fatty acid oxidation and to maintain energy balance. Recent studies from our PPG team (Drs Kliewer and Mangelsdorf) have demonstrated that overexpression of FGF21 in mice extends lifespan. Interestingly, FGF21 is also expressed in thymus, however, the impact of FGF21 on ability of thymus to produce T cells and immune system decline during aging is unknown. A major phenotype of age-related thymic degeneration is loss of thymic epithelial cells, emergence of fibroblasts and the accumulation of ectopic lipid within thymus. This project is based on our recent findings that FGF21 overexpression delays aging of thymus and reduces the generation of ectopic lipid and inflammation in thymus. Based on our novel findings that FGF21 improves thymic function, the central hypothesis of this proposal is that approaches to enhance FGF21 signaling in thymic epithelial cells (TECs) will rejuvenate thymic lymphopoiesis and expand T cell repertoire diversity during aging. Aim1 will be using loss and gain of function models where FGF21 signaling is specifically targeted to thymic epithelial cell. This aim will test the hypothesis that FGF21 supports thymic function during aging through autocrine and paracrine action on thymic stromal cells. Aim2 will test the impact of FGF21 on thymic rejuvenation in aged mice and will test the hypothesis that FGF21 mimics a molecular state that signals energy deficit which reprograms thymic stromal cell metabolism towards utilization of lipid as energy substrate. Aim3 will evaluate thymus-independent effects of FGF21on systemic age-related inflammation. Thus, the long term goal of this project is to develop FGF21 agonists as clinical intervention to lower inflammation and improve T cell dependent immune-surveillance in elderly.